The facultative intracellular bacterial pathogen, Francisella tularensis, can cause severe pneumonia and death following the inhalation of very small numbers of infectious particles. For this reason, F. tularensis is considered a primary biological warfare agent. Acquired host immunity against this pathogen is predominantly T-cell-mediated rather than humoral. An attenuated strain of F. tularensis is an effective live vaccine against virulent strains of the pathogen. However, this strain retains its virulence for mice, and might cause disease if administered to immunocompromised individuals. Thus, for mass-vaccination purposes, a defined fast-acting acellular vaccine would be preferable to the current live vaccine. Our institute has developed a novel vaccine delivery technology based on liposomes manufactured from the total polar lipids of various Archaebacteria. These liposomes termed, archaeosomes, generate robust cell-mediated immune responses to model antigens entrapped within them, without the aid of any additional immune stimulants. Recently, we showed that a short peptide antigen of another intracellular pathogen, Listeria monocytogenes, packaged in archaeosomes, provides a high level of protective immunity against this pathogen in a murine listeriosis model after only a single vaccination. Because multiple studies indicate that the same host defenses are needed to combat F. tularensis and L. monocytogenes, it is likely that appropriate antigens of the former pathogen encapsulated in archaeosomes will provide effective acellular vaccines. This proposal will explore this possibility. It is expected that the findings from the proposed studies will be applicable to the development of acellular vaccines against other intracellular respiratory pathogens such as Mycobacterium tuberculosis, and Chlamydia pneumoniae.